. Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins. Dev Dyn. 2012 Feb;241(2):415-25. PubMed.


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  1. The paper by Liao et al. suggests a revision of our understanding of the biological role of the amyloid precursor protein and its relationship to vasculature. The authors use gene trapping in zebrafish where GFP coding sequences become fused to the coding sequences of endogenous genes.

    They found one gene trap in a zebrafish APP gene. (To be exact, the gene is APPA, that is one of two genes derived from duplication of an ancestral APP ortholog.) They also found a gene trap in the zebrafish ortholog of APLP2. In both cases, the protein fusions that result consist of most of the extracellular domains of the zebrafish Appa and Aplp2 proteins with GFP. As the authors show, the fusion proteins accumulate in vasculature, which is where antibody studies have previously suggested that APP is expressed. However, using whole mount in-situ transcript hybridization, the authors show that the APPA and APLP2 genes do not appear to be transcribed in the vasculature. Instead, the genes appear to be expressed in neurons.

    This result suggests that our understanding of the cellular sites of APP expression in humans may be inaccurate. As the authors state, “Although there is one report of human APP protein localization in endothelial cells of the gut … there are no reports in the literature of APP mRNA expression in vascular cells.” The authors point out that expression of the zebrafish APPB gene (the other gene derived from the ancestral APP ortholog) has been observed in vasculature, but when I look at the relevant paper (Lee and Cole, 2007), only APPB expression in the dorsal aorta is certain, while it is possible that expression in other blood vessels results from the nature of the promoter fusion transgene used. (Indeed, Lee and Cole cannot detect expression of endogenous APPB transcripts in most vasculature by in-situ transcript hybridization despite the sensitivity of this technique, and they do not show expression in neural vasculature.)

    The data from Liao et al. also suggest that the movement of extracellular fragments of APP from neurons to the vasculature may be a form of communication between neurons and vasculature. In the study by Gama Sosa et al., 2010, we saw that human familial AD mutant forms of PSEN1 expressed only in transgenic mouse neurons nevertheless cause changes in neural microvasculature. It is tempting to speculate that PSEN1’s role in release of amyloid-β could be part of a mechanism of communication between the neurons and microvasculature.


    . Generation of transgenic zebrafish expressing green fluorescent protein under control of zebrafish amyloid precursor protein gene regulatory elements. Zebrafish. 2007 Winter;4(4):277-86. PubMed.

    . Age-related vascular pathology in transgenic mice expressing presenilin 1-associated familial Alzheimer's disease mutations. Am J Pathol. 2010 Jan;176(1):353-68. PubMed.

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